1-(1-acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) as a potent, selective, and orally available soluble epoxide hydrolase inhibitor with efficacy in rodent models of hypertension and dysglycemia

Abstract

1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea 14a (AR9281), a potent and selective soluble epoxide hydrolase inhibitor, was recently tested in a phase 2a clinical setting for its effectiveness in reducing blood pressure and improving insulin resistance in pre-diabetic patients. In a mouse model of diet induced obesity, AR9281 attenuated the enhanced glucose excursion following an intraperitoneal glucose tolerance test. AR9281 also attenuated the increase in blood pressure in angiotensin-II-induced hypertension in rats. These effects were dose-dependent and well correlated with inhibition of the sEH activity in whole blood, consistent with a role of sEH in the observed pharmacology in rodents.

Figure 1

Evaluation of 14a (AR9281) in DIO mouse model. Left is the blood glucose levels over time following an intraperitoneal administration in a typical experiment. Right is the whole blood sEH activity following the last dose of the study.

Scheme 1

Preparation of piperidinyl ureas 14: a) NH₂OH^·HCl, EtOH, Pyridine, reflux, 1h, 82% b) RaNi, MeOH, rt, 4 h, 83% c) p-nitrophenyl chloroformate, DCM, 2 h, 87% d) DCM, rt, 12 h, 82% e) THF, reflux, 12 h, 85% f) TFA, DCM, rt, 12 h, 88% g) Ac₂O or MeSO₂Cl, DCM, rt, 18 h, 70–90%

Figure 3

Structures 1–7

Figure 4

Structure 14a